The unifying goal of this proposal is to break down the hypermutation process into separate events, which can then be studied in mechanistic detail. Each aim proposes an independent strategy directed toward this goal. The aims are: 1. study the role of DNA lesions in hypermutation; 2. determine the function of mismatch repair in hypermutation; 3. develop extrachromosomal substrates for active, targeted hypermutation; and 4. identify and characterize activities essential for the regulation or initiation of hypermutation. The significance of these aims, when achieved, is that they will provide an understanding of this key process. This will also provide molecular targets which can be manipulated to enhance or modulate diseases states, including autoimmune diseases.